title: Recessive TTN truncating mutations define novel forms of core myopathy with heart disease.
abstract: Core myopathies (CM), the main non-dystrophic myopathies in childhood, remain genetically unexplained in many cases. Heart disease is not considered part of the typical CM spectrum. No congenital heart defect has been reported, and childhood-onset cardiomyopathy has been documented in only two CM families with homozygous mutations of the TTN gene. TTN encodes titin, a giant protein of striated muscles. Recently, heterozygous TTN truncating mutations have also been reported as a major cause of dominant dilated cardiomyopathy. However, relatively few TTN mutations and phenotypes are known, and titin pathophysiological role in cardiac and skeletal muscle conditions is incompletely understood. We analyzed a series of 23 families with congenital CM and primary heart disease using TTN M-line-targeted sequencing followed in selected patients by whole-exome sequencing and functional studies. We identified seven novel homozygous or compound heterozygous TTN mutations (five in the M-line, five truncating) in 17% patients. Heterozygous parents were healthy. Phenotype analysis identified four novel titinopathies, including cardiac septal defects, left ventricular non-compaction, Emery-Dreifuss muscular dystrophy or arthrogryposis. Additionally, in vitro studies documented the first-reported absence of a functional titin kinase domain in humans, leading to a severe antenatal phenotype. We establish that CM are associated with a large range of heart conditions of which TTN mutations are a major cause, thereby expanding the TTN mutational and phenotypic spectrum. Additionally, our results suggest titin kinase implication in cardiac morphogenesis and demonstrate that heterozygous TTN truncating mutations may not manifest unless associated with a second mutation, reassessing the paradigm of their dominant expression.
authors.affiliation: Inserm, U787 Myology group, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Chauveau
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bonnemann
authors.forename: Cedric
authors.initials: C
authors.lastname: Julien
authors.forename: Ay Lin
authors.initials: AL
authors.lastname: Kho
authors.forename: Harold
authors.initials: H
authors.lastname: Marks
authors.forename: Beril
authors.initials: B
authors.lastname: Talim
authors.forename: Philippe
authors.initials: P
authors.lastname: Maury
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Arne-Bes
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Uro-Coste
authors.forename: Alexander
authors.initials: A
authors.lastname: Alexandrovich
authors.forename: Anna
authors.initials: A
authors.lastname: Vihola
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schafer
authors.forename: Beth
authors.initials: B
authors.lastname: Kaufmann
authors.forename: Livija
authors.initials: L
authors.lastname: Medne
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.forename: A Reghan
authors.initials: AR
authors.lastname: Foley
authors.forename: Mariarita
authors.initials: M
authors.lastname: Santi
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloglu
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
authors.forename: Mathias
authors.initials: M
authors.lastname: Gautel
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreiro
mesh_terms: D000293:Adolescent; D018389:Codon, Nonsense; D064211:Connectin / Q000235:genetics* / Q000378:metabolism; D003241:Consanguinity; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020512:Myopathy, Central Core / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D064211:Connectin; C577285:TTN protein, human